Stilbene Synthesis by Mizoroki–Heck Coupling Reaction Under Microwave Irradiation

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An effective Pd nanocatalyst in aqueous media: stilbene synthesis by Mizoroki–Heck coupling reaction under microwave irradiation

Carolina S. García, Paula M. Uberman and Sandra E. Martín*

Full Research Paper Open Access

Address: Beilstein J. Org. Chem. 2017, 13, 1717–1727. INFIQC-CONICET- Universidad Nacional de Córdoba, Departamento doi:10.3762/bjoc.13.166 de Química Orgánica, Facultad de Ciencias Químicas, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA, Córdoba, Received: 25 April 2017 Argentina Accepted: 04 August 2017 Published: 18 August 2017 Email: Sandra E. Martín* - [email protected] Associate Editor: L. Vaccaro

* Corresponding author © 2017 García et al.; licensee Beilstein-Institut. License and terms: see end of document. Keywords: aqueous reaction medium; MAOS; Mizoroki–Heck reaction; Pd nanoparticle; sustainable organic synthesis

Abstract Aqueous Mizoroki–Heck coupling reactions under microwave irradiation (MW) were carried out with a colloidal Pd nanocatalyst stabilized with poly(N-vinylpyrrolidone) (PVP). Many stilbenes and novel heterostilbenes were achieved in good to excellent yields starting from aryl bromides and different olefins. The reaction was carried out in a short reaction time and with low catalyst loading, leading to high turnover frequency (TOFs of the order of 100 h−1). The advantages like operational simplicity, high robustness, efficiency and turnover frequency, the utilization of aqueous media and simple product work-up make this protocol a great option for stilbene syntheses by Mizoroki–Heck reaction.

Introduction Palladium-catalyzed reactions have emerged as an important basic types of Pd-catalyzed reactions, particularly the vinyl- tool for organic synthesis. Among them, cross-coupling and ation of aryl/vinyl halides or triflates [7-10], explored not only coupling reactions have been broadly applied for C–C and in the inter- and intramolecular version [2,11-13], but also in C–heteroatom bond formation [1-6]. These reactions have been domino [14] and asymmetric catalytic processes [15]. Due to its proven to be powerful and attractive synthetic methods due to versatility, the Mizoroki–Heck reaction is extensively em- their high selectivity and tolerance to a wide range of func- ployed in the synthesis of pharmaceutical, agrochemical and tional groups on both coupling partners. The Mizoroki–Heck natural products, and continues to attract attention within the reaction and related chemistry occupy a special place among the synthetic chemists’ community [16-18].

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From an economic and environmental standpoint, it is highly temperature via direct electroreduction of aqueous H2PdCl4 in desirable to develop more environmentally friendly synthetic the presence of poly(N-vinylpirrolidone) (PVP) [46,47]. These methodologies. Several studies were dedicated to the design of Pd NPs exhibited highly efficient catalytic activity in a novel catalytic system, that are more accessible, robust, effi- Suzuki–Miyaura coupling reactions [46,47] and nitroaromatic cient and ligand-free [19]. In that sense, nanoparticles (NPs) of hydrogenations [48] in aqueous medium. Outstanding perfor- transition metals have been introduced as eco-catalysts in mance of these PVP-Pd NPs in the coupling reaction was ob- several reactions [20]. The NPs became a useful tool for catalyt- served, reaching high turnover numbers (TON up 104–105) in ic transformations due to their excellent performance, which is the presence of aryl iodides and bromides. Additionally, the related to their small size and a high surface-to-volume ratio performance of the NPs was briefly examined for the [21-25]. Moreover, they are relatively easy to prepare and can Mizoroki–Heck reaction with haloacetophenones [47]. As a be obtained in different size and morphology by essentially remarkable feature of this nanocatalyst, besides its great cata- controlling the synthetic method and experimental conditions. lyst activity and compatibility with aqueous reaction media, is As a result of the excellent catalytic activity of NPs, they can be that it can be used without previous purification processes. used under mild and, in some cases, in environmental sustain- Consequently, as a part of our ongoing interest in developing able conditions. In particular, Pd NPs have been well-estab- green reaction conditions for organic syntheses; we herein lished as catalysts in the Mizoroki–Heck coupling reaction, ob- report an extensive study on the catalytic application of the taining the desired products in good to high yields, finding electrochemical synthesized PVP-Pd NPs for Mizoroki–Heck some examples in aqueous solution and under microwave coupling reaction. By the efficient coupling reaction with aryl (MW) irradiation [26-36]. Besides these studies, there is consid- bromides, many stilbenes and novel hetero-stilbenes were ob- erable room for improvements of the reported catalytic systems, tained employing the Pd NPs in aqueous medium under rela- which may involve high catalyst loadings (>1 mol %), toxic sol- tively mild conditions, using MW irradiation. vents, or limited application scope of iodoarenes and olefins [19]. Results and Discussion The PVP-Pd NPs of a mean diameter of 10 nm were obtained Along with the increasing awareness about the development of using a platinum electrode, characterized as previously re- sustainable catalysts, additional efforts should be made to ported, and used without additional purification [46,47]. In a address also sustainable reaction conditions; like employing previous work the PVP-Pd NPs synthesized using a vitreous ecological solvents and alternative energy input among others carbon electrode were tested on the Mizoroki–Heck reaction aspects [37,38]. Water represents a very attractive medium as a with 4-iodo- or 4-bromoacetophenone and styrene [47]. The result of its advantages as solvent (nontoxic, not flammable, best result with 4-bromoacetophenone was accomplished when cheap and readily available), the use of water or aqueous the reaction was performed under MW irradiation for systems as solvent in organic synthesis to replace hazardous and 10 minutes using 0.2 mol % of Pd, affording the (E)-stilbene expensive organic solvents have been explored [39,40]. Various product in 98% yield. In order to further explore the scope of catalytic systems have been reported for the Mizoroki–Heck the PVP-Pd NPs-catalyzed Mizoroki–Heck coupling, a system- reaction in aqueous medium [41-43]. However, a drawback of atic study of the reaction was carried out with a wide range of using water is related to the limited solubility of the reactants, substrates and olefins. Based on our previous results [47], and leading to less efficient reactions. To solve this problem several other reported examples of Mizoroki–Heck coupling reactions systems have been developed by using co-solvents, surfactants, that use MW irradiation as alternative energy input pressure reactors or heating the reaction mixture by MW irradi- [26,28,36,49], the reaction of 4-bromoacetophenone (1a) and ation [44]. Under MW irradiation conditions, not only the rate styrene (2a) as coupling reagents was initially selected to of organic reactions could be increased, and better selectivities screening the reaction conditions (Table 1). In this case, the of the products achieved, but also the homogeneous mixing of reactions were performed with 0.1 mol % of Pd, in a mixture of the reactants in water could be enhanced, on the basic of the H2O/alcohol (3:1) as solvent under MW irradiation, employing efficient ability to absorb MW energy by water [44]. The use of a dynamic heating method at fixed temperature in a sealed water in combination with MW heating for Heck coupling reac- vessel. The results are summarized in Table 1. tions has been reported, using a phase-transfer agent and focusing on the employment of ultralow catalyst concentrations A general screening was performed to determine the optimal [45]. reaction time, the identity and presence of a co-solvent (ethanol,

isopropanol, ethylene glycol) and the best base (K2CO3, Recently, we reported the electrochemical synthesis of stable Pd Na2CO3, K3PO4, sodium acetate (NaOAc)). In a first approach, NPs by using platinum or vitreous carbon electrodes at room time optimization was performed by using K2CO3 as base, at

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Table 1: Reaction condition optimizations.a

Entry Solvent Base t (min) Yield (%)b

1 H2O/EtOH K2CO3 1 65 2 H2O/EtOH K2CO3 5 92 3 H2O/EtOH K2CO3 10 100 c 4 H2O/EtOH K2CO3 10 88 5 H2O K2CO3 10 23 6 H2O/iPrOH K2CO3 10 100 7 H2O/ethylene glycol K2CO3 10 54 d 8 H2O/EtOH K2CO3 10 100 9 H2O/EtOH Na2CO3 10 100 10 H2O/EtOH K3PO4 10 93 11 H2O/EtOH NaOAc 10 54 12 H2O/EtOH – 10 <5 e 13 H2O/EtOH K2CO3 10 73 aReaction conditions: 0.25 mmol of 4-bromoacetophenone (1a), 0.30 mmol of styrene (2a), 0.5 mmol of the base, 0.1 mol % of Pd, 2 mL of the mixed solvent 3:1, 130 °C MW (dynamic heating method) in a sealed vessel. bGC yields. The yields reported represent at least the average of two reactions. c d e Pd loading of 0.05 mol %. Tap water. Catalyst source: H2PdCl4 0.5 mM + 16 g/L PVP.

130 °C by MW irradiation (entries 1–3, Table 1). The highest system was evaluated. For that, the Mizoroki–Heck coupling catalytic activity of PVP-Pd NPs was obtained after 10 minutes, reaction was carried out with a homogeneous mixture based on when the yield of stilbene 3 achieved 100% (entry 3, Table 1). H2PdCl4 and PVP (the same solution employed to obtain PVP- Reducing the catalyst loading (0.05 mol %) leads to a decrease Pd NPs by electroreduction, entry 13, Table 1). Under the same of product yield, however, to a very respectable 88% yield reaction conditions, this in situ arranged catalytic system proved (entry 4, Table 1). To achieve a complete conversion with this to be less active than the electrochemically preformed Pd NPs. Pd loading 20 min of MW irradiation were required. The influ- Additionally, Pd NPs of an average size of (4 ± 1) nm and ence and identity of the co-solvent were also explored (entries spherical shape were obtained when they were prepared from

5–8, Table 1). This screening showed that the presence of an the same H2PdCl4 and PVP aqueous solution using MW irradia- alcohol was required to obtain the products in high yields (entry tion (see Supporting Information File 1). The morphology and 5, Table 1). Ethanol or isopropanol can be used in this system to size of the Pd NPs was determined by TEM micrographs. achieve quantitatively the desired products; however, when Unfortunately, these MW-synthesized NPs proved to be inac- ethylene glycol was used lower yields were reached (entries 3, 6 tive as catalysts in the Mizoroki–Heck coupling reaction be- and 7, Table 1). On the other hand, the use of tap water had no tween 1a and 2a in aqueous medium. negative effect on the catalytic activity of the catalyst (entry 8, Table 1). When the nature of the base was evaluated, it was ob- Thus, the PVP-Pd NPs electrochemically preformed showed a served that inorganic bases gave high yields of stilbene 3 high catalytic activity in the Mizoroki–Heck reaction, employ-

(entries 9 –12, Table 1). K2CO3 and Na2CO3 could be used to ing nontoxic solvents and without the need to previously activa- obtain the products in excellent yields (entries 3 and 9, Table 1). tion [19] or treatment of the catalyst. Furthermore, this nanocat- A slightly lower yield of stilbene 3 was observed employing alyst exhibited an outstanding activity for aryl bromides. We

K3PO4 (93%; entry 10, Table 1). As it was expected, when the previously reported that [47] in the coupling of 1a with 2a reaction was carried out in the absence of a base, there was no under the same reaction conditions with conventional heating conversion of substrate 1a (entry 12, Table 1). and in the presence of 0.2 mol % of PVP-Pd NPs only 39% yield of product 3 was achieved after 24 hours. Thus, syner- Taking into account that several Pd NPs could be synthesized gism between MW and Pd NPs can lead to really efficient by MW irradiation [49], the in situ formation of NPs in the and sustainable catalytic systems. It is noteworthy that

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besides the high conversion, the TOF (h−1) values found for aryl halides 1a–h and olefins 2a–c were screened, employing Mizoroki–Heck coupling reactions to obtain stilbene 3 (TOF the best reaction conditions above obtained (0.5 mmol of −1 ≈11000 h , entry 2, Table 1) were relative high for aryl bro- K2CO3, H2O/EtOH, at 130 ºC, Table 2). mides [50,51], even by comparison of the present protocol with other catalytic systems with Pd NPs under MW heating [52]. In all cases, clean and high selective reactions to obtain the trans-products were achieved. In order to extend the catalytic applications of this PVP-Pd NPs in the Mizoroki–Heck reaction, a substrate screening was By using styrene (2a) and aryl bromides with electron-with- carried out to determine the reaction scope and particularly the drawing groups as coupling partners, such as 4-bromoaceto- synthetic applications of this nanocatalyst. Thus, a variety of phenone (1a) and 4-bromobenzophenone (1b), the reactions

Table 2: Mizoroki–Heck reaction of aryl halides with olefins catalyzed by PVP-Pd NPs.a

Entry 1 2 % Pd Product Yield (%)b TOF (h−1) t (min) (TON)c T (°C)

0.1 6000 1 1a 2a 10 100 (1000) 130 3

0.1 5100 2 1b 2a 10 85 (850) 130

0.2 1920 3 1c 2a 15 96 (480) 130 5

0.2 1960 4 1d 2a 10 98 (490) 130

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Table 2: Mizoroki–Heck reaction of aryl halides with olefins catalyzed by PVP-Pd NPs.a (continued)

0.2 1620 5 1e 2a 15 81 (405) 150 7

0.2 1620 6 1f 2a 15 81 (405) 150 8

0.2 1200 7 1g 2a 15 60 (300) 150 9

0.05 19920 8 1h 2a 5 83 (1660) 130 10

0.1 3560 9 1a 2b 15 89 (890) 130 11

0.1 3480 10 1b 2b 15 87 (870) 150

0.2 1920 11 1c 2b 15 96 (480) 150 13

0.2 1920 12 1d 2b 15 96 (480) 150

0.2 800 13 1a 2c 15 40 (200) 130

15 a Reaction conditions: 0.25 mmol of aryl halide, 0.30 mmol of olefin, 0.5 mmol of K2CO3, 2 mL of the mixed H2O/EtOH 3:1, MW (dynamic heating method) in a sealed vessel. bGC yields. The yields reported represent at least the average of two reactions. cTOF (turnover frequency, mol substrate converted per mol of Pd per hour). TON (turnover number, mol substrate converted per mol of Pd).

were carried out in short times, employing low catalyst loading, Despite that the synthesis of substituted heteroaryl derivatives is obtaining the (E)-stilbenes 3 and 4 with excellent yields and of great importance, only few examples employing heteroaryl selectivity (entries 1 and 2, Table 2). halides in the Mizoroki–Heck reaction were reported [53]. This

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might be attributed to electronic aspects or poison by the hetero- 4-Bromoacetophenone (1a) and 1-bromo-3,5-dimethoxyben- atom to the active Pd species [54]. However, when the cou- zene (1d) were chosen to react with tributyl(vinyl)stannane pling reaction with 3-bromoquinoline (1c) was carried out with (16). In both cases, the desired stilbenes 17 and 18 were ob- PVP-Pd NPs as catalyst, the desired product 5 was obtained in tained in good yield and in short reaction time under MW irra- excellent yield (entry 3, Table 2). The reaction conditions de- diation, besides the different electronic characteristic of sub- veloped to obtain stilbene 5 are better than the previously re- strates 1a and 1d (entries 1 and 2, Table 3). Thus, it was found ported ones (higher yields, short reaction time and more benign that the PVP-Pd NPs were effective to catalyze two different solvent) [55]. reactions in a consecutive way. High yields and selectivity of the coupling products were obtained. These examples provide In addition, aryl bromides with electron-donating substituents the first report about consecutive Stille–Heck reactions in were evaluated in the Mizoroki–Heck reaction catalyzed by aqueous media under MW irradiation. PVP-Pd NPs (entries 4–7, Table 2). As general trend, with styrene (2a) as coupling partner, aryl bromides with an electron- Once the scope of the reaction was established, we were inter- withdrawing group or containing a nitrogen heterocycle (entries ested in investigating the synthetic applicability of this catalyst 1–3, Table 2) react better than aryl bromides with electron-do- in a natural product synthesis. For this purpose, the reaction be- nating groups (entries 4–7, Table 2). In the latter cases, higher tween aryl bromide 1d and 4-acetoxystyrene (2d) was studied temperatures, or a slight increase in reaction time and catalyst to obtain (E)-pterostilbene (19, Scheme 1). loading were needed to obtain the desired (E)-stilbenes 6–9 in good yields. When an ortho-substituted arene, 1g, was used, Several derivatives of polyphenolic stilbenes as (E)-pterostil- product 9 was obtained in only moderate yield compared with bene are natural products, which present an interesting biologi- para-substituted stilbene 8 synthesized under the same condi- cal activity [59]. Under the above mentioned reaction conditions (entries 6 and 7, Table 2). This behavior can be tions (E)-pterostilbene (19) was obtained in moderate yield, but explained by the steric hindrance caused by the methylene with a high TOF value considering the use of deactivated aryl group in ortho-position. The coupling of styrene with bromide 1d. Additionally, cleavage of the acetyl group in a substrate bearing an acidic proton, 4-iodophenol (1h), reagent 2d occurred in the same reaction media without any ad- was found to proceed efficiently, obtaining a high TOF of ditional steps. This issue should not be a trouble for the reac- 19920 h−1 (entry 8, Table 2). Unfortunately, it was not tion in view of the coupling takes place properly in the pres- possible to successfully accomplish the Mizoroki–Heck ence of hydroxy groups. The synthetic procedures proposed for coupling with aryl chlorides under many tested reaction condi- this type of stilbenes involves several steps, in which a Wittig tions. reaction followed by different metal-catalyzed reactions and harsh conditions are usually required [60-62]. In our case, the Additionally, the heterocyclic alkene 4-vinylpyridine (2b) was desired product was obtained under environmentally friendly used as a coupling partner in the presence of aryl bromides reaction conditions and in a short reaction time. 1a–d. Even though olefin 2b was shown to be slightly less reactive than styrene (2a), the heteroaromatic coupling products Thus, the PVP-Pd NPs proved to be an effective catalyst to were afforded in excellent yields (entries 9–12, Table 2). By perform the coupling reaction between a wide range of aryl bro- this methodology, new heteroaromatic olefins 11–13 were syn- mides and different alkenes. Besides, with demanding sub- thesized. The reaction with the symmetric gem-substituted strates like heterocycles, ortho-substituted and non-activated olefin 1,1-diphenylethylene (2c) and 4-bromoacetophenone (1a) aryl halides, very good results were achieved. gave the trisubstituted olefin 15 in moderate yield (40%, entry 13, Table 2) [56]. Finally, the reusability of PVP-Pd NPs was evaluated in the reaction between 4-bromoacetophenone (1a) and styrene (2a). On the other hand, and in order to further explore the scope of In our previous reports [46-48], it was exposed that a PVP-Pd the PVP-Pd NPs catalyst, the synthesis of stilbene derivatives NPs aqueous dispersion exhibited a high stability, and for that by Pd-tandem reactions was carried out. Some synthetic reason, the Pd NPs cannot be separated by a physical technique. methods employing consecutive Pd Hiyama–Heck coupling Any attempt to separate the nanocatalyst from reaction media reactions have been reported to obtain a variety of stilbene de- by centrifugation, precipitation or organic extraction eventually rivatives [55,57,58]. In our case, consecutive Pd-catalyzed lead to a dramatic drop of the catalytic activity. As a result of Stille–Heck coupling reactions were explored in the presence of this, and in order to perform the reuse experiment, repeated runs PVP-Pd NPs under MW irradiation to obtain the stilbenes. The on the same batch were performed; reusing the reaction mix- results are summarized in Table 3. ture with the PVP-Pd nanocatalyst. By this procedure in both,

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Table 3: Stille–Heck tandem reaction of aryl halides with tributyl(vinyl)stannane.a

Entry 1 % Pd Product Yield (%)b TOF (h−1) (TON)c

3320 1 1a 0.1 83 (1660)

1600 2 1d 0.2 80 (800)

18 a Reaction conditions: 0.5 mmol of aryl halide, 0.25 mmol of tributyl(vinyl)stannane (16), 1 mmol of K2CO3, 4 mL of H2O/EtOH 3:1, 130 °C MW (dynamic heating method) in a sealed vessel during 30 minutes. bGC yields. The yields reported represent at least the average of two reactions. cTON (turnover number, mol substrate converted per mol of Pd). TOF (turnover frequency, mol substrate converted per mol of Pd per hour).

Scheme 1: Synthesis of (E)-pterostilbene (19) catalyzed by PVP-Pd NPs.

Suzuki–Miyaura coupling reaction [46] and nitroaromatic hydrogenation [48], the PVP-Pd NPs catalytic system exhibited high catalytic activity after five cycles. In the Heck–Mizoroki coupling reaction under MW irradiation, once the reaction was completed, a new batch of reagents was added to the reaction tube and it was once more heated by MW irradiation for the needed time. After that, a GC analysis of the reaction mixture was performed and product 3 was quantified (Figure 1).

Although the activity of PVP-Pd NPs slightly decreased in the second cycle, stilbene 3 was still obtained in good yields after five cycles of the Heck–Mizoroki coupling reaction. The initial Figure 1: Reuse experiments of PdNPs in the coupling reaction be- drop could be explained by taking into account that the product tween 4-bromoacetophenone (1a) and styrene (2a). Time: 1º cycle: and substrates are not soluble in the aqueous media causing a 10 min; 2º cycle: 20 min; 3º cycle: 30 min, 4º cycle: 30 min, 5º cycle: 30 min. non-homogeneous heating and stirring of the system [63].

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TEM micrograph of PVP-Pd NPs before and after one catalytic All solvents were of analytical grade and distilled before use. cycle was performed. The physical separation of NPs was All reactions were carried out under air atmosphere. Silica gel carried out by centrifugation as previously reported [48]. The (0.063–0.200 mm) was used for column chromatography. An comparison of both TEM micrographs disclosed that the orig- Autolab PGSTAT100 (ECO CHEMIE) potentiostat–galvano- inal PVP-Pd NPs [(9 ± 2) nm] clump to larger aggregates after stat was used for both, the potentiodynamic experiments and the the first catalytic cycle, providing NPs with a mean diameter of galvanostatic pulses. Gas chromatographic analysis were per- (20 ± 10) nm with high dispersion in size (Figures S1 and S2, formed on a gas chromatograph with a flame ionization Supporting Information File 1). However, these bigger NPs detector, and equipped with the following columns: HP-5 were still active as catalysts, since with this larger NPs several 25 m × 0.20 mm × 0.25 μm column. 1H NMR and 13C NMR catalytic cycles were performed (Figure 1). The morphology of were conducted on a high resolution spectrometer Bruker the NPs like a “blackberry” appeared not to be modified, and Advance 400, in CDCl3 as solvent. Gas chromatographic/ probably this structure is responsible for the activity since it mass spectrometer analyses were carried out on a leaves enough surface available to perform the catalytic reac- GC–MS QP 5050 spectrometer equipped with a VF-5 ms, tion. 30 m × 0.25 mm × 0.25 μm column. Melting points were determined with an electrical instrument. MW-induced reactions Conclusion were performed in a CEM Focused Microwave TM Synthesis In summary, the PVP-Pd NPs exhibit an outstanding catalytic System, Model Discover single mode instrument. Transmission activity in the Mizoroki–Heck reaction under environmentally electron microscopy was conducted in a JEM-Jeol 1120 oper- friendly reaction conditions employing aqueous solvent ating at 80 kV, at the IFFIVE Research Institute, INTA, and MW irradiation. Under the optimized conditions Córdoba, Argentina. In order to characterize NPs by TEM, sam-

(0.05–0.25 mol % Pd NPs, 2 equiv of K2CO3, 2 mL of H2O/ ples were prepared through depositing a drop of colloidal PVP- EtOH 3:1, at 130–150 ºC), the corresponding stilbenes and Pd NPs solution on a formvar-carbon-coated cooper grid and novel heterostilbenes could be obtained in good to excellent dried at room temperature. The total content of Pd was deter- yields (40–100%) from aryl/heteroaryl bromides and different mined by atomic absorption in a Perkin Elmer Analyst 600, olefins. The stilbenes were achieved with high selectivity for using ET (electro thermal mode with graphite furnace) at the trans-products in short reaction time leading to high reaction ISIDSA Institute, Universidad Nacional de Córdoba, Córdoba, rates (TOFs of the order of 103) for bromide derivatives. When Argentina. Aqueous solutions were prepared from analytical less reactive electrophiles were used, the catalytic performance grade chemicals and Milli-Q Millipore water. depended on the Pd NPs loading. Fundamental properties in- cluding high robustness, efficiency and TOFs, mild reaction Synthesis of Pd nanoparticles suspension by conditions, utilization of aqueous media as a green solvent and electrochemical reduction simple product work-up make this catalytic system favorable The electrochemical synthesis of PVP-Pd NPs was carried out from the environmental and economic point of view. Reusabili- as previously reported [46]. The experiments were achieved in a ty experiments of the reaction mixture showed that PVP-Pd NPs glass electrochemical cell equipped with a Pt disc working elec- maintain their catalytic activity after an initial little drop for at trode (geometric area = 0.0746 cm2), a very large area sheet of least five cycles. Moreover, the PVP-Pd NPs catalyst system Pt (counter electrode) and a saturated calomel reference elec- was applied to a tandem Stille–Heck reaction. trode (SCE). The Pd NPs dispersions were obtained through

Pd(II) electroreduction in KNO3 (0.1 M) and H2PdCl4 Experimental (0.5 × 10−3 M) solutions (pH 3.0) by applying a current density Materials and methods pulse at the Pt electrode in the presence of PVP as the stabi- 4-Bromoacetophenone (1a), 4-bromobenzophenone (1b), lizing agent under solution stirring. The galvanostatic synthesis 3-bromoquinoline (1c) 1-bromo-3,5-dimethoxybenzene (1d), of Pd NPs was performed by applying to the platinum electrode 4-bromoanisole (1e), 4-bromotoluene (1f), 2-bromotoluene a current density pulse from 0 to a cathodic value of (1g), 4-iodophenol (1h), styrene (2a), 4-vinylpyridine (2b), 150 mA/cm2, during 600 s. Vigorous stirring of the solution 1,1-diphenylethylene (2c), 4-acetoxystyrene (2d), (1000 rpm) with a magnetic stirrer was kept during the galvano- tributyl(vinyl)stannane (16). K3PO4, Na2CO3, K2CO3, sodium static electrolysis. After completion of the reaction the aqueous acetate (AcONa), ethanol 98% (EtOH), isopropanol (iPrOH), dispersion of Pd NPs was placed in a 25 mL volumetric flask to ethylene glycol and anhydrous Na2SO4 were used without be used as catalyst solution for Mizoroki–Heck coupling reac- purification. Electrolytes for the electrochemical experiments tion without further purification. Average dimensions contain KNO3, H2PdCl4 and PVP polymer [poly-(N- and shapes of Pd NPs were determined by transmission vinylpyrrolidone)] (MW 10000 Da), HCl 35%. electron microscope (TEM) images and the total content of Pd

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in the colloidal suspensions was determined by atomic absorp- rubber cap and heated at 130 °C for 30 minutes under MW irra- tion. diation (fixed temperature method) using air cooling. After that, the reaction was cooled to room temperature, extracted three Synthesis of Pd nanoparticle suspensions times with ethyl acetate (15 mL each) and dried with an- under MW irradiation hydrous Na2SO4. The stilbene products 17 and 18 were puri- In a 10 mL MW tube equipped with a magnetic stirring bar, fied by silica gel column chromatography. The products were −4 1 13 0.125 mL of H2PdCl4 2 mM (2.5 × 10 mmol), 16 g/L of PVP characterized by H NMR, C NMR, and GC–MS. All the 10000 Da (14.24 mg), 0.5 mL of ethanol, and 1.75 mL of bidis- spectroscopic data were in agreement with those previously re- tilled H2O were added. Then, the reaction tube was sealed with ported for the following compounds: (E)-1,1'-(ethene-1,2- a rubber cap and heated at 130 °C for 10 minutes under MW ir- diylbis(4,1-phenylene))diethanone (17) [68] and (E)-1,2- radiation (fixed temperature method) using air cooling. Aver- bis(3,5-dimethoxyphenyl)ethane (18) [69]. age dimensions and shape of Pd NPs were determined by transmission electron microscope (TEM) images. Catalyst reusability experiments in the MW-assisted Mizoroki–Heck coupling Representative procedure for MW-assisted reaction Mizoroki–Heck coupling reactions The reusability of PVP-Pd NPs was evaluated in the The experimental procedure for MW-assisted Mizoroki–Heck Mizoroki–Heck coupling reaction between 4-bromoaceto- coupling reactions was carried out analogously to the proce- phenone (1a) and styrene (2a). Initially, the first reaction cycle dure previously reported [47]. Into a 10 mL MW tube equipped was carried out following the procedure above described, em- with a magnetic stirring bar, aryl halide 1a–h (0.25 mmol), ploying 0.1 mol % of Pd NPs dispersion and heating by MW ir-

K2CO3 (0.5 mmol), olefin 2a–d (0.3 mmol), ethanol (0.5 mL) radiation for 10 minutes. After that, the same mixture was and water (to obtain a total volume of 2 mL taking into account reused by addition of fresh amounts of reactants: 4-bromo- the volume of Pd NPs solution) were added. Finally, the re- acetophenone (0.125 mmol), K2CO3 (0.25 mmol), styrene quired volume of the Pd NPs dispersion was added. Then, the (0.15 mmol), ethanol (0.5 mL) and water (0.35 mL), and heated reaction tube was sealed with a rubber cap and heated at again for the needed time. This procedure was repeated until the 130–150 °C for 5–30 minutes under MW irradiation (fixed tem- desired cycle was reached. In the final cycle, the reaction was perature method) using air cooling. After that, the reaction mix- processed as previously described. ture was cooled to room temperature, extracted three times with ethyl acetate (15 mL each) and dried with anhydrous Na2SO4. Supporting Information The stilbene products 3–15 were purified by silica gel column chromatography. The products were characterized by 1H NMR, Supporting Information File 1 13 C NMR, and GC–MS. All spectroscopic data were in agree- TEM images of Pd nanoparticles, characterization data, and ment with those previously reported for the following com- NMR spectra. pounds: (E)-1-(4-styrylphenyl)ethanone (3) [64], (E)-phenyl(4- [http://www.beilstein-journals.org/bjoc/content/ styrylphenyl)methanone (4) [64], (E)-3-styrylquinoline (5) [55], supplementary/1860-5397-13-166-S1.pdf] (E)-1,3-dimethoxy-5-styrylbenzene (6) [64], (E)-1-methoxy-4- styrylbenzene (7) [64], (E)-1-methyl-4-styrylbenzene (8) [65], (E)-1-methyl-2-styrylbenzene (9) [65], (E)-4-styrylphenol (10) Acknowledgements [66], (E)-4-(3,5-dimethoxystyryl)pyridine (14) [67], 1-(4-(2,2- The research was supported by CONICET, FONCyT and diphenylvinyl)phenyl)ethanone (15) [56], and (E)-4-(3,5- SECyT - UNC. C.S.G. gratefully acknowledges CONICET for dimethoxystyryl)phenol or pterostilbene (19) [60]. the fellowships. We thank Dr. Luis Pérez and Dr. Gabriela Lacconi (INFIQC, CONICET-Universidad Nacional de Representative procedure for the Córdoba) for assistance with electrochemical experiments. MW-assisted Stille–Heck coupling reactions Analogously to the procedure described in [47], into a 10 mL References MW tube equipped with a magnetic stirring bar, aryl bromide 1. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066. doi:10.1021/cr9903048 1a, 1d (0.5 mmol), K2CO3 (1 mmol), tributyl(vinyl)stannane (16, 0.25 mmol), ethanol (1 mL) and water (to obtain a total 2. De Meijere, A.; Diederich, F., Eds. Metal-Catalyzed Cross-Coupling Reaction; Wiley-VCH Verlag GmbH: Weinheim, Germany, 2008. volume of 4 mL taking into account the volume of Pd NPs solu- 3. New Trends in Cross-Coupling: Theory and Applications. In RSC tion) were added. Finally, the required volume of the Pd NPs Catalysis Series Nº 21; Colacot, T., Ed.; RSC: Cambridge, U.K., 2015. dispersion was added. Then, the reaction tube was sealed with a

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